Degeneration of auditory neurons due to the loss of cochlear hair cells and endogenous trophic support they provide can lead to successive hearing impairments. Growing evidence indicates that treatment with neurotrophic agents, such as brain-derived neurotrophic factor (BDNF), is sufficient to maintain survival of auditory neurons after loss of hair cells. However, cessation of neurotrophin treatment may result in accelerated neuronal loss compared to untreated cochleas. Therefore, finding a means of long-term delivery of neurotrophic agents to auditory neurons in the diseased ear is essential. Conventional delivery strategies, often separated from cochlear implantation as a clinical treatment for the diseased ear, come with numerous problems, including uneven delivery profiles, limited temporal delivery profiles, and difficulty with retrieval. Therefore, the overall objective of this project is to develop a "living" cochlear implant that incorporates long-term, sustained, and targeted therapeutic-agent delivery strategies based on a tissue-engineering concept. Specifically, a cochlear implant combined with living neurotrophin- releasing cells, will be evaluated in this project for long-term delivery of neurotrophins. Two specific aims will be achieved during the course of the project. Specific Aim 1 is to define the neurotrophin-releasing profiles of the implant in vitro. Specific Aim 2 is to evaluate the therapeutic efficacy of the implant in preventing nerve degeneration secondary to hair-cell loss in animal models. The proposed project will be completed in two years. Fulfillment of this project will directly benefit hearing-impaired patients by providing clinically applicable biomedical devices that possess all the merits of current treatments for the diseased ear yet are more efficacious and provide more flexibility in treatment options for hearing-impaired patients at different stages of disease. In addition, the proposed project will benefit the research fields of auditory functional restoration and bioengineering in general by establishing guidelines for incorporating engineering principles into life science and medicine. These guidelines will enhance therapy for diseases and promote multidisciplinary collaborations among engineers, biologists, and clinical surgeons. Successful fulfillment of this project will directly benefit deaf patients by providing them with clinically applicable biomedical devices that possess all the merits of current treatments for the diseased ear yet are more efficacious and provide more flexibility in the treatment options at different stages of the diseases. [unreadable] [unreadable] [unreadable]